Title of project: Neural plasticity during acclimatization to hypoxia. Chronic hypoxia increases the hypoxic ventilatory response (HVR) by increasing the CV sensitivity of carotid body chemoreceptors and the sensitivity of respiratory centers in the CNS to sensory input from carotid bodies. These changes in the HVR involve O2-sensitive gene expression and other molecular signals in carotid bodies and the CNS. Ventilatory drive in normoxia is also increased by chronic hypoxia but the mechanisms for this are unknown. However, central chemoreceptors may be involved because arterial PCO2 is regulated at a lower level after acclimatization. Recently, we discovered that the increased HVR and increased normoxic ventilatory drive after chronic hypoxia could be blocked by microinjecting glutamate receptor antagonists into the nucleus tractus solitarius (NTS). The NTS is important for respiratory control as the site of the primary synapse from carotid body chemoreceptors, and as 1 of many CO2-sensitive central chemoreceptor sites. We hypothesize that (1) chronic hypoxia increases sensitivity to carotid body sensory input and increases normoxic ventilatory drive by changes in NMDA and non-NMDA glutamate receptors in the NTS, (2) such neural plasticity is caused by O2-sensitive (e.g. HIF-1a, reactive O2 species) and O2-independent mechanisms (e.g. increased glutamate), and (3) central chemoreceptors in the NTS play a unique role in ventilatory acclimatization to hypoxia compared to CO2-sensitive chemoreceptors at other sites in the brainstem. We will test these hypotheses by (1) microinjecting NMDA and AMPA receptor agonists and antagonists in awake and anesthetized rats while measuring respiratory motor output, (2) measuring effects of chronic hypoxia and neural stimulation on mRNA and protein levels for glutamate receptors in the NTS, (3) studying central chemoreceptors in rat medullary slices in vitro, and (4) using transgenic mouse models of conditional HIF-1a deletion in the CNS. Experiments are designed to elucidate general principles of signaling for adaptive changes to chronic hypoxia in the brain, and ultimately how changes in ventilatory control may contribute to hypoxemia in patients with chronic lung disease.